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Background: Patients with gastroparesis and related disorders have symptoms including early satiety, postprandial fullness and bloating. Buspirone, a 5-HT 1 receptor agonist, may improve fundic accommodation., Aim: To determine if buspirone treatment improves early satiety and postprandial fullness in patients with symptoms of gastroparesis., Methods: This 4-week multi-centre clinical trial randomised patients with symptoms of gastroparesis and moderate-to-severe symptoms of fullness (Gastroparesis Cardinal Symptom Index [GCSI] early satiety/postprandial fullness subscore [ES/PPF]) to buspirone (10 mg orally) or placebo three times per day. The primary outcome was a change in the ES/PPF from baseline to 4 weeks. The primary analysis was per protocol intention-to-treat ANCOVA of between-group baseline vs. 4-week differences (DoD) in ES/PPF adjusted for baseline ES/PPF. Results are reported using both nominal and Bonferroni (BF) p values., Results and Conclusions: Ninety-six patients (47 buspirone, 49 placeboes; 92% female, 50% delayed gastric emptying, 39% diabetic) were enrolled. There was no between-groups difference in the 4-week ES/PPF primary outcome: -1.16 ± 1.25 (SD) on buspirone vs -1.03 ± 1.29 (SD) on placebo (mean DoD: -0.11 [95% CI: -0.68, 0.45]; p = 0.69). Buspirone performed better than placebo in patients with severe-to-very severe bloating at baseline compared to patients with none to moderate: (ES/PPF DoD = -0.65 vs. 1.58, p TX*GROUP  = 0.003; p BF  = 0.07). Among individual GCSI symptoms, only bloating appeared to improve with buspirone vs. placebo., Conclusions: Patients with moderate-to-severe early satiety/postprandial fullness and other symptoms of gastroparesis did not benefit from buspirone treatment to improve the ES/PPF primary outcome compared with placebo. There was a suggestion of the benefit of buspirone in patients with more severe bloating., Trial Registration: ClinicalTrials.gov NCT0358714285., (© 2023 John Wiley & Sons Ltd.)

Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects., (© 2023. The Author(s).)

Rationale: Irritable bowel syndrome (IBS) is a chronic and debilitating functional disorder of the gastrointestinal tract manifested by abdominal pain and bowel habit dysregulation. The pathophysiology is complex and management targets symptom resolution. Therapeutic interventions range from dietary modification, psychological interventions, exercise, to the use of antispasmodics, antibiotics, and antidepressants. Anecdotal reports have suggested that buspirone may be beneficial in the treatment of functional dyspepsia and IBS and its physiological effect of reducing gastric tone provides a rational for its benefit., Patient Concerns: A 28-year-old man with unremarkable past medical and psychiatric history presented with worsening abdominal pain, bloating, and bowel movement dysregulation of over 6-year duration., Diagnoses: Physical examination revealed mild distension and discomfort on deep palpation. Thorough blood investigations, stool analysis and culture, and imaging were unremarkable except for the detection of mucus with stool. The patient was diagnosed with irritable bowel syndrome with mixed habits., Interventions: Dietary adjustment and a range of medications (mebeverine, simethicone, loperamide, rifaximin, sertraline and amitriptyline) yielded unsatisfactory response of were not tolerated. Buspirone was eventually introduced., Outcomes: Buspirone was associated with a significant and sustained improvement in IBS symptoms and quality of life., Lessons: This case suggests that buspirone was effective in treating refractory IBS. Further research is needed to assess the role of buspirone in IBS management., Competing Interests: Competing interests: PMH reports personal fees from Janssen, Lundbeck, Otsuka, NewBridge Pharmaceuticals, and Sunovion, outside the submitted work. The other authors report no conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.

Study Design: Retrospective analysis of treated inpatients compared to expected neurorecovery from a propensity score-matched national database cohort., Objective: Evaluate the effectiveness of buspirone on clinical neurorecovery following traumatic SCI when started during acute inpatient rehabilitation., Setting: University-based hospital in Boston, USA., Methods: Chart review yielded thirty-one individuals with acute, traumatic SCI treated with buspirone during inpatient rehabilitation from 2011-2017. Propensity score matching to a cohort of individuals from the spinal cord injury model systems (SCIMS) national database was completed. Changes in upper extremity motor score (UEMS), lower extremity motor score (LEMS), American Spinal Injury Association Impairment Scale (AIS), neurological level of injury (NLI), and functional impairment measure (FIM) from admission to discharge and discharge to 1 year were computed and compared between matched pairs (buspirone and mean national SCIMs cohort). A local control cohort not treated with buspirone was similarly compared to a matched mean national SCIMs group to identify location-specific effects., Results: From admission to discharge from inpatient rehabilitation, 95% confidence intervals of changes in UEMS (-2.43 to +2.78), LEMS (-1.02 to +6.02), AIS (-0.04 to +0.35), NLI (-0.42 to +1.08), and FIM (-4.42 to +6.40) were not significantly different between those individuals who received buspirone and their propensity-matched SCIMS cohort. Similarly, changes in these metrics were not significantly different at 1-year follow up. Buspirone group individuals with initial clinically complete SCI demonstrated a higher 1-year conversion rate to incomplete injury (6 out of 14; 42.9%) compared to the matched national SCIMS cohort (14 out of 70; 21.2%, p = 0.047) though this was not significantly different from non-buspirone local controls (p = 0.25)., Conclusions: Retrospective analysis shows no statistically significant difference in gross markers of neurorecovery following acute traumatic SCI when buspirone is initiated indiscriminately during acute inpatient rehabilitation. In individuals with clinically complete SCI, findings suggest possible increased rates of 1-year conversion to incomplete injury.

Serotonergic agents can improve the recovery of motor ability after a spinal cord injury. Herein, we compare the effects of buspirone, a 5-HT 1A receptor partial agonist, to fluoxetine, a selective serotonin reuptake inhibitor, on forelimb motor function recovery after a C4 bilateral dorsal funiculi crush in adult female rats. After injury, single pellet reaching performance and forelimb muscle activity decreased in all rats. From 1 to 6 weeks after injury, rats were tested on these tasks with and without buspirone (1-2 mg/kg) or fluoxetine (1-5 mg/kg). Reaching and grasping success rates of buspirone-treated rats improved rapidly within 2 weeks after injury and plateaued over the next 4 weeks of testing. Electromyography (EMG) from selected muscles in the dominant forelimb showed that buspirone-treated animals used new reaching strategies to achieve success after the injury. However, forelimb performance dramatically decreased within 2 weeks of buspirone withdrawal. In contrast, fluoxetine treatment resulted in a more progressive rate of improvement in forelimb performance over 8 weeks after injury. Neither buspirone nor fluoxetine significantly improved quadrupedal locomotion on the horizontal ladder test. The improved accuracy of reaching and grasping, patterns of muscle activity, and increased excitability of spinal motor-evoked potentials after buspirone administration reflect extensive reorganization of connectivity within and between supraspinal and spinal sensory-motor netxcopy works. Thus, both serotonergic drugs, buspirone and fluoxetine, neuromodulated these networks to physiological states that enabled markedly improved forelimb function after cervical spinal cord injury., (© 2020. The American Society for Experimental NeuroTherapeutics, Inc.)

Background: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action., Objectives: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults., Search Methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data., Selection Criteria: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo., Data Collection and Analysis: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability., Main Results: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence)., Authors' Conclusions: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

Background: Globally, cannabis use is prevalent and widespread. There are currently no pharmacotherapies approved for treatment of cannabis use disorders.This is an update of a Cochrane Review first published in the Cochrane Library in Issue 12, 2014., Objectives: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or no pharmacotherapy (supportive care) for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use., Search Methods: We updated our searches of the following databases to March 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and Web of Science., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs involving the use of medications to treat cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in people diagnosed as cannabis dependent or who were likely to be dependent., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis.Abstinence at end of treatment was no more likely with Δ 9 -tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence).There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported.Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence).Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness., Authors' Conclusions: There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.

Methylphenidate is commonly use for the treatment of attention deficit hyperactivity disorder (ADHD), but its long term use was found to produce hepatic necrosis in mice. Purpose of this study was to investigate that co-administration of buspirone (drug which attenuates methylphenidate induced sensitization) may attenuate methylphenidate-induced hepatotoxic effects and to determine the effect of challenge dose of haloperidol (D2 antagonist that blocks the effects of methylphenidate in case of intoxication) on SGPT and SGOT levels in methylphenidate treated rats. Estimation of SGPT and SGOT were performed using kit method. Prolong oral administration of methylphenidate at a dose of 2.0 mg/kg/day, buspirone at a dose of 10 mg/kg/day, their co-administration and challenge dose of haloperidol (1 mg/kg i.p.) in rats increased SGPT concentration and decreased SGOT concentration, effect is more pronounced in methylphenidate treated rats and potentiate with administration of haloperidol challenge dose. In conclusion our analysis showed that methylphenidate and challenge dose of haloperidol is associated with elevation of SGPT in rats, which is attenuate in co-administration of methylphenidate buspirone treated rats. To quantify the risk of methylphenidate-induced hepatic injury and role of buspirone to reduce the injury further pharmacoepidemiological investigations are required.

Background: Prolonged treatment with benzodiazepines is common practice despite clinical recommendations of short-term use. Benzodiazepines are used by approximately 4% of the general population, with increased prevalence in psychiatric populations and the elderly. After long-term use it is often difficult to discontinue benzodiazepines due to psychological and physiological dependence. This review investigated if pharmacological interventions can facilitate benzodiazepine tapering., Objectives: To assess the benefits and harms of pharmacological interventions to facilitate discontinuation of chronic benzodiazepine use., Search Methods: We searched the following electronic databases up to October 2017: Cochrane Drugs and Alcohol Group's Specialised Register of Trials, CENTRAL, PubMed, Embase, CINAHL, and ISI Web of Science. We also searched ClinicalTrials.gov, the WHO ICTRP, and ISRCTN registry, and checked the reference lists of included studies for further references to relevant randomised controlled trials., Selection Criteria: We included randomised controlled trials comparing pharmacological treatment versus placebo or no intervention or versus another pharmacological intervention in adults who had been treated with benzodiazepines for at least two months and/or fulfilled criteria for benzodiazepine dependence (any criteria)., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included 38 trials (involving 2543 participants), but we could only extract data from 35 trials with 2295 participants. Many different interventions were studied, and no single intervention was assessed in more than four trials. We extracted data on 18 different comparisons. The risk of bias was high in all trials but one. Trial Sequential Analysis showed imprecision for all comparisons.For benzodiazepine discontinuation, we found a potential benefit of valproate at end of intervention (1 study, 27 participants; risk ratio (RR) 2.55, 95% confidence interval (CI) 1.08 to 6.03; very low-quality evidence) and of tricyclic antidepressants at longest follow-up (1 study, 47 participants; RR 2.20, 95% CI 1.27 to 3.82; low-quality evidence).We found potentially positive effects on benzodiazepine withdrawal symptoms of pregabalin (1 study, 106 participants; mean difference (MD) -3.10 points, 95% CI -3.51 to -2.69; very low-quality evidence), captodiame (1 study, 81 participants; MD -1.00 points, 95% CI -1.13 to -0.87; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -3.57 points, 95% CI -5.34 to -1.80; very low-quality evidence), tricyclic antidepressants (1 study, 38 participants; MD -19.78 points, 95% CI -20.25 to -19.31; very low-quality evidence), and flumazenil (3 studies, 58 participants; standardised mean difference -0.95, 95% CI -1.71 to -0.19; very low-quality evidence) at end of intervention. However, the positive effect of paroxetine on benzodiazepine withdrawal symptoms did not persist until longest follow-up (1 study, 54 participants; MD -0.13 points, 95% CI -4.03 to 3.77; very low-quality evidence).The following pharmacological interventions reduced symptoms of anxiety at end of intervention: carbamazepine (1 study, 36 participants; MD -6.00 points, 95% CI -9.58 to -2.42; very low-quality evidence), pregabalin (1 study, 106 participants; MD -4.80 points, 95% CI -5.28 to -4.32; very low-quality evidence), captodiame (1 study, 81 participants; MD -5.70 points, 95% CI -6.05 to -5.35; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -6.75 points, 95% CI -9.64 to -3.86; very low-quality evidence), and flumazenil (1 study, 18 participants; MD -1.30 points, 95% CI -2.28 to -0.32; very low-quality evidence).Two pharmacological treatments seemed to reduce the proportion of participants that relapsed to benzodiazepine use: valproate (1 study, 27 participants; RR 0.31, 95% CI 0.11 to 0.90; very low-quality evidence) and cyamemazine (1 study, 124 participants; RR 0.33, 95% CI 0.14 to 0.78; very low-quality evidence). Alpidem decreased the proportion of participants with benzodiazepine discontinuation (1 study, 25 participants; RR 0.41, 95% CI 0.17 to 0.99; number needed to treat for an additional harmful outcome (NNTH) 2.3 participants; low-quality evidence) and increased the occurrence of withdrawal syndrome (1 study, 145 participants; RR 4.86, 95% CI 1.12 to 21.14; NNTH 5.9 participants; low-quality evidence). Likewise, magnesium aspartate decreased the proportion of participants discontinuing benzodiazepines (1 study, 144 participants; RR 0.80, 95% CI 0.66 to 0.96; NNTH 5.8; very low-quality evidence).Generally, adverse events were insufficiently reported. Specifically, one of the flumazenil trials was discontinued due to severe panic reactions., Authors' Conclusions: Given the low or very low quality of the evidence for the reported outcomes, and the small number of trials identified with a limited number of participants for each comparison, it is not possible to draw firm conclusions regarding pharmacological interventions to facilitate benzodiazepine discontinuation in chronic benzodiazepine users. Due to poor reporting, adverse events could not be reliably assessed across trials. More randomised controlled trials are required with less risk of systematic errors ('bias') and of random errors ('play of chance') and better and full reporting of patient-centred and long-term clinical outcomes. Such trials ought to be conducted independently of industry involvement.

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects' genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Background: Tension-type headaches are a common source of pain and suffering. Our purpose was to assess the efficacy of tricyclic (TCA) and tetracyclic antidepressants in the prophylactic treatment of tension-type headache., Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the ISI Web of Science, and clinical trial registries through 11 March 2017 for randomized controlled studies of TCA or tetracyclic antidepressants in the prevention of tension-type headache in adults. Data were pooled using a random effects approach., Key Results: Among 22 randomized controlled trials, eight included a placebo comparison and 19 compared at least two active treatments. Eight studies compared TCAs to placebo, four compared TCAs to selective serotonin reuptake inhibitors (SSRIs), and two trials compared TCAs to behavioral therapies. Two trials compared tetracyclics to placebo. Single trials compared TCAs to tetracyclics, buspirone, spinal manipulation, transcutaneous electrical stimulation, massage, and intra-oral orthotics. High-quality evidence suggests that TCAs were superior to placebo in reducing headache frequency (weighted mean differences (WMD): -4.8 headaches/month, 95% CI: -6.63 to -2.95) and number of analgesic medications consumed (WMD: -21.0 doses/month, 95% CI: -38.2 to -3.8). TCAs were more effective than SSRIs. Low-quality studies suggest that TCAs are superior to buspirone, but equivalent to behavioral therapy, spinal manipulation, intra-oral orthotics, and massage. Tetracyclics were no better than placebo for chronic tension-type headache., Conclusions: Tricyclic antidepressants are modestly effective in reducing chronic tension-type headache and are superior to buspirone. In limited studies, tetracyclics appear to be ineffective in the prophylactic treatment of chronic tension-type headache.

Background: Approximately 20% of stroke patients experience clinically significant levels of anxiety at some point after stroke. Physicians can treat these patients with antidepressants or other anxiety-reducing drugs, or both, or they can provide psychological therapy. This review looks at available evidence for these interventions. This is an update of the review first published in October 2011., Objectives: The primary objective was to assess the effectiveness of pharmaceutical, psychological, complementary, or alternative therapeutic interventions in treating stroke patients with anxiety disorders or symptoms. The secondary objective was to identify whether any of these interventions for anxiety had an effect on quality of life, disability, depression, social participation, caregiver burden, or risk of death., Search Methods: We searched the trials register of the Cochrane Stroke Group (January 2017). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2017, Issue 1: searched January 2017); MEDLINE (1966 to January 2017) in Ovid; Embase (1980 to January 2017) in Ovid; the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1937 to January 2017) in EBSCO; and PsycINFO (1800 to January 2017) in Ovid. We conducted backward citation searches of reviews identified through database searches and forward citation searches of included studies. We contacted researchers known to be involved in related trials, and we searched clinical trials registers for ongoing studies., Selection Criteria: We included randomised trials including participants with a diagnosis of both stroke and anxiety for which treatment was intended to reduce anxiety. Two review authors independently screened and selected titles and abstracts for inclusion., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias. We performed a narrative review. We planned to do a meta-analysis but were unable to do so as included studies were not sufficiently comparable., Main Results: We included three trials (four interventions) involving 196 participants with stroke and co-morbid anxiety. One trial (described as a 'pilot study') randomised 21 community-dwelling stroke survivors to four-week use of a relaxation CD or to wait list control. This trial assessed anxiety using the Hospital Anxiety and Depression Scale and reported a reduction in anxiety at three months among participants who had used the relaxation CD (mean (standard deviation (SD) 6.9 (± 4.9) and 11.0 (± 3.9)), Cohen's d = 0.926, P value = 0.001; 19 participants analysed).The second trial randomised 81 participants with co-morbid anxiety and depression to paroxetine, paroxetine plus psychotherapy, or standard care. Mean levels of anxiety severity scores based on the Hamilton Anxiety Scale (HAM-A) at follow-up were 5.4 (SD ± 1.7), 3.8 (SD ± 1.8), and 12.8 (SD ± 1.9), respectively (P value < 0.01).The third trial randomised 94 stroke patients, also with co-morbid anxiety and depression, to receive buspirone hydrochloride or standard care. At follow-up, the mean levels of anxiety based on the HAM-A were 6.5 (SD ± 3.1) and 12.6 (SD ± 3.4) in the two groups, respectively, which represents a significant difference (P value < 0.01). Half of the participants receiving paroxetine experienced adverse events that included nausea, vomiting, or dizziness; however, only 14% of those receiving buspirone experienced nausea or palpitations. Trial authors provided no information about the duration of symptoms associated with adverse events. The trial of relaxation therapy reported no adverse events.The quality of the evidence was very low. Each study included a small number of participants, particularly the study of relaxation therapy. Studies of pharmacological agents presented details too limited to allow judgement of selection, performance, and detection bias and lack of placebo treatment in control groups. Although the study of relaxation therapy had allocated participants to treatment using an adequate method of randomisation, study recruitment methods might have introduced bias, and drop-outs in the intervention group may have influenced results., Authors' Conclusions: Evidence is insufficient to guide the treatment of anxiety after stroke. Further well-conducted randomised controlled trials (using placebo or attention controls) are required to assess pharmacological agents and psychological therapies.

Morphine and other opioids are among the most effective prescription medications for the treatment of pain. Addiction and hyperalgesia associated with their long-term use limits the clinical utility of these drugs. In view of a role of somatodendritic serotonin-1A receptors in addiction and analgesic effects of morphine, the present study concerns effects of co-use of buspirone, a partial agonist at the serotonin-1A receptor, on reinforcing, hyperalgesic, and motor effects of morphine in rats. A dose of morphine (7.5 mg/kg) producing moderate effects on motor activity and analgesia, and buspirone (doses of 0, 1.0, and 2.0 mg/kg) were injected intraperitoneally. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. Acute administration of morphine decreased motor activity and reduced pain perception. Repeated administration was reinforcing in the CPP paradigm and was associated with hyperalgesia and tolerance in motor depressant effects of morphine. These effects of repeated morphine administration were blocked in rats cotreated with buspirone. Pain perception was also slightly reduced in rats repeatedly treated with higher doses of buspirone. The findings are important for improving and extending therapeutic medications for pain., Perspective: The present study shows an important role of serotonin-1A receptors in morphine-induced hyperalgesia and addiction. It shows that buspirone, a prescription medicine for anxiety and depression can block addictive and hyperalgesic effects of morphine. Clinicians should consider buspirone as adjunctive therapy with morphine to improve therapeutic medications in pain., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered., Objective: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward., Discussion: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.

Background: Acute administration of the oral 5-HT1A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc)., Methods: Thirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged., Results: Eight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively)., Conclusion: Our findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT02363478 Registered: 21-02-2014.

Background: Anxiety disorders are common in early adulthood, but general population studies concerning the treatment adequacy of anxiety disorders taking into account appropriate pharmacological and psychological treatment are scarce. The aims of this study were to examine treatments received for anxiety disorders in a Finnish general population sample of young adults, and to define factors associated with receiving minimally adequate treatment and with dropping out from treatment., Methods: A questionnaire containing several mental health screens was sent to a nationally representative two-stage cluster sample of 1894 Finns aged 19 to 34 years. All screen positives and a random sample of screen negatives were invited to a mental health assessment including a SCID interview. For the final diagnostic assessment, case records from mental health treatments for the same sample were obtained. This article investigates treatment received, treatment adequacy and dropouts from treatment of 79 participants with a lifetime anxiety disorder (excluding those with a single specific phobia). Based on all available information, receiving antidepressant or buspirone medication for at least 2 months with at least four visits with any type of physician or at least eight sessions of psychotherapy within 12 months or at least 4 days of hospitalization were regarded as minimally adequate treatment for anxiety disorders. Treatment dropout was rated if the patient discontinued the visits by his own decision despite having an adequate treatment strategy according to the case records., Results: Of participants with anxiety disorders (excluding those with a single specific phobia), 41.8 % had received minimally adequate treatment. In the multivariate analysis, comorbid substance use disorder was associated with antidepressant or buspirone medication lasting at least 2 months. Those who were currently married or cohabiting had lower odds of having at least four visits with a physician a year. None of these factors were associated with the final outcome of minimally adequate treatment or treatment dropout. Participants with comorbid personality disorders received and misused benzodiazepines more often than others., Conclusions: More efforts are needed to provide adequate treatment for young adults with anxiety disorders. Attention should be paid to benzodiazepine prescribing to individuals with personality disorders.

Unlabelled: The agitation crisis in the awakening phase after traumatic brain injury (TBI) is one of the most difficult behavioral disorders to alleviate. Current treatment options are heterogeneous and may involve excessive sedation. Practice guidelines are required by professionals in charge of TBI patients. Few reviews were published but those are old and based on expert opinions. The purpose of this work is to propose evidence-based guidelines to treat the agitation crisis., Methods: The elaboration of these guidelines followed the procedure validated by the French health authority for good practice recommendations, close to the Prisma statement. Guidelines were elaborated on the basis of a systematic and critical review of the literature., Results: Twenty-eight articles concerning 376 patients were analyzed. Recommendations are: when faced with an agitation crisis, the management strategy implies to search for an underlying factor that should be treated such as pain, acute sepsis, and drug adverse effect (expert opinion). Physical restraints should be discarded when possible (expert opinion). Neuroleptic agent with a marketing authorization can be used in order to obtain a quick sedation so as to protect the patient from himself, closed ones or the healthcare team but the duration should be as short as possible (expert opinion). The efficacy of beta-blockers and antiepileptics with mood regulation effects like carbamazepine and valproate yield the most compelling evidence and should be preferably used when a background regimen is envisioned (grade B for beta-blocker and C for antiepileptics). Neuroleptics, antidepressants, benzodiazepines, buspirone may be prescribed but are considered second-line treatments (expert opinion)., Conclusion: This study provides a strategy for treating the agitation crisis based on scientific data and expert opinion. The level of evidence remains low and published data are often old. New studies are essential to validate results from previous studies and test new drugs and non-pharmaceutical therapies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Substance abuse and anxiety is a common comorbid dyad and an example of so-called dual diagnosis in psychiatry. Comorbidity of anxiety and addictive disorders may be due to interdependence of these states as well as common predisposing factors and pathogenic mechanisms. There are various medicines in the treatment of anxiety associated with substance abuse, including benzodiazepines, calcium channel modulators, non-benzodiazepine anxiolytics, antidepressants and antipsychotics. One of the best approaches to the treatment of chronic anxiety disorders in drug treatment clinic is a long course of treatment with antidepressants, primarily with selective serotonin reuptake inhibitors as first line preparations. Such medications as pregabalin, buspirone, etifoxine and alimemazine are also of interest for the treatment of dual diagnosis patients.

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4-12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis., Competing Interests: NM has a confidential disclosure and consulting agreement with Janssen Research and Development, LLC. PG has been PI on three recent drug trials for Demerx and is a consultant for Kinex Pharma. The remaining authors declare no conflict of interest.

Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left-right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the epithalamus in the regulation of stress responses in zebrafish., (Copyright © 2015 the authors 0270-6474/15/3515847-13$15.00/0.)

Background: Anxiety disorders are a potentially disabling group of disorders that frequently co-occur with alcohol use disorders. Comorbid anxiety and alcohol use disorders are associated with poorer outcomes, and are difficult to treat with standard psychosocial interventions. In addition, improved understanding of the biological basis of the conditions has contributed to a growing interest in the use of medications for the treatment of people with both diagnoses., Objectives: To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders., Search Methods: Review authors searched the specialized registers of The Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDANCTR, to January 2014) and the Cochrane Drugs and Alcohol Group (CDAG, to March 2013) for eligible trials. These registers contain reports of relevant randomized controlled trials (RCT) from: the Cochrane Central Register of Controlled Trials (CENTRAL, all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). Review authors ran complementary searches on EMBASE, PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database (ETOH) (to August 2013). We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform (to August 2013). We screened reference lists of retrieved articles for additional studies., Selection Criteria: All true RCTs of pharmacotherapy for treating anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review., Data Collection and Analysis: A systematic review is a standardised evaluation of all research studies that address a particular clinical issue.Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi(2) and I(2) heterogeneity statistics., Main Results: We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting.Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male.There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline., Authors' Conclusions: The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication.Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

Background and Purpose: Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1 A receptor, but these drugs have been reported to worsen PD features and are known to produce '5-HT syndrome', symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia., Experimental Approach: Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1 A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1 A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia., Key Results: Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome., Conclusions and Implications: The results suggest that compounds that indirectly facilitate 5-HT1 A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1 A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile., (© 2014 The British Pharmacological Society.)

Buspirone, a nonbenzodiasepine anxiolytic, is a partial serotonin 5-HT1A-receptor agonist, D2-autoreceptor antagonist and low affinity 5-HT2-receptor agonist. This medication is used for treatment of generalized anxiety disorder though it may be prescribed in other anxiety states, primarily, panic disorder, sociophobia and depression. Buspirone seems to be potential in treatment of other neurological and mental disorders (tardive dyskinesia in Parkinson's disease, ataxia, behavioral disorders, cranial/brain injuries, dementia, attention-deficit hyperactivity disorder).

The introduction into clinical practice of new and highly effective antidepressants has certainly helped to resolve the problem of depression therapy. However, achieving a complete remission, which is a key point for therapy in depressed patients, remains a difficult task. It is known that a significant number of patients do not respond to antidepressants. So, special attention has been paid in recent years towards investigation of methods that could improve the treatment effectiveness in depressive. In this review presents the results of clinical trials of buspirone as an adjunctive therapy in cases with previous ineffective use of antidepressants in patients with major depressive disorder.

Objective: To explore the efficacy of spitomine (buspirone) in the combined therapy of panic disorder, we studied the dynamics of clinical parameters and personality traits associated with development and maintenance of panic disorder during the treatment., Material and Methods: Thirty patients of a treatment setting for out-patients with panic disorder were enrolled in the study. Patients received combined treatment with spitomine (buspirone) in the dose of 30 mg/daily (10 mg three times a day) during 6 weeks and individual short-term direct cognitive-behavioral therapy. Anxiety and panic symptoms were measured with HARS, CGI, MADRS and STAI-A., Results: There was a significant reduction in panic and anxiety symptoms (by 50% on the HARS) that reached on average 9.73 scores to the end of the study. This finding indicates the absence of anxiety and, therefore, therapeutic efficacy of the treatment. Scores on state anxiety of STAI-A were significantly lower compared to baseline though the level of anxiety remained relatively high. The partial decrease in trait anxiety, though its level was high as well, was noted., Conclusion: The combined therapy of panic disorder with spitomine (buspirone) and cognitive-behavioral therapy is an optimal treatment, though not without the limitations of short-term methods. Good tolerability of the drug allowed all patients to complete the study.

Buspirone, a 5-HT1A receptor agonist, and environmental enrichment (EE) enhance cognition and reduce histopathology after traumatic brain injury (TBI) in adult rats, but have not been fully evaluated after pediatric TBI, which is the leading cause of death in children. Hence, the aims of this study were to assess the efficacy of buspirone alone (Experiment 1) and in combination with EE (Experiment 2) in TBI postnatal day-17 male rats. The hypothesis was that both therapies would confer cognitive and histological benefits when provided singly, but their combination would be more efficacious. Anesthetized rats received a cortical impact or sham injury and then were randomly assigned to receive intraperitoneal injections of buspirone (0.08 mg/kg, 0.1 mg/kg, and 0.3 mg/kg) or saline vehicle (1.0 mL/kg) 24 h after surgery and once daily for 16 days (Experiment 1). Spatial learning and memory were assessed using the Morris water maze (MWM) on post-operative days 11-16, and cortical lesion volume was quantified on day 17. Sham controls for each condition were significantly better than all TBI groups. In the TBI groups, buspirone (0.1 mg/kg) enhanced MWM performance versus vehicle and buspirone (0.08 mg/kg and 0.3 mg/kg) (p<0.05) and reduced lesion volume relative to vehicle (p=0.038). In Experiment 2, buspirone (0.1 mg/kg) or vehicle was combined with EE after TBI, and the data were compared to the standard (STD)-housed groups from Experiment 1. EE lead to a significant enhancement of spatial learning and a reduction in lesion size versus STD. Moreover, the combined treatment group (buspirone+EE) performed markedly better than the buspirone+STD and vehicle+EE groups, which suggests an additive effect and supports the hypothesis. The data replicate previous studies assessing these therapies in adult rats. These novel findings may have important rehabilitation-relevant implications for clinical pediatric TBI.

Background: Panic disorder is common in the general population. It is often associated with other psychiatric disorders, such as drug dependence, major depression, bipolar disorder, social phobia, specific phobia and generalised anxiety disorder. Azapirones are a class of drugs used as anxiolytics. They are associated with less drowsiness, psychomotor impairment, alcohol potentiation and potential for addiction or abuse than benzodiazepines. However, azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear. It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder., Objectives: To assess the effects of azapirones on panic disorder in adults, specifically:1. to determine the efficacy of azapirones in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison with placebo;2. to review the acceptability of azapirones in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate adverse effects of azapirones in panic disorder with or without agoraphobia, including general prevalence of adverse effects, compared with placebo., Search Methods: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, search date: 10th January 2014), which includes relevant randomised controlled trials from The Cochrane Library (all years), MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-)., Selection Criteria: Randomised controlled trials that compared azapirones with placebo for panic disorder in adults., Data Collection and Analysis: Three review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information., Main Results: Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses., Authors' Conclusions: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder.

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

The article reviews current publications on the epidemiology, psychopathology, diagnostic criteria and comorbidity of most frequently encountered in the practice anxiety disorders: generalized anxiety disorder and panic disorder. Special attention is paid to the pharmacotherapy of anxiety disorders in the aspect of efficacy of main classes of drugs, including buspirone. The results of clinical trials of buspirone are presented.

The aim of the study was to evaluate the evidence that serotonin1A (5-HT1A) receptor partial agonists of the azapirone class, which are not antipsychotic, have benefits for adjunctive treatment of overall psychopathology, positive and negative symptoms for patients with schizophrenia. We carried out a systematic review of the literature available through PubMed, Cochrane Library, PsycINFO and Google Scholar during September 2012, followed by a meta-analysis of randomized placebo-controlled trials. Risk ratio (RR), 95% confidence intervals (CI) and standardized mean difference (s.m.d.) were calculated. Four studies, involving 163 patients with schizophrenia, met inclusion criteria: buspirone: three trials and 137 patients; tandospirone: one trial and 26 patients. As adjunctive therapy, 5-HT1A partial agonists were significantly superior to placebo for overall improvement in psychopathology (s.m.d. = -0.46, CI = -0.79 to -0.13, p = 0.006, N = 4, n = 149) and marginally more effective to improve positive symptoms (s.m.d. = -0.31, CI = -0.64 to 0.01, p = 0.06, N = 4, n = 149). However, 5-HT1A partial agonists were not more efficacious than placebo as adjunctive therapy for improving negative symptoms (s.m.d. = -0.09, CI = -0.60 to 0.42, p = 0.72, N = 4, n = 149). In addition, there was no significant difference in discontinuation rates between 5-HT1A partial agonists and placebo (all cause: RR = 0.98, CI = 0.49-1.98, p = 0.96, N = 4, n = 153, side-effects: RR = 1.96, CI = 0.54-7.19, p = 0.31, N = 4, n = 153). 5-HT1A partial agonists as adjunctive therapy improved overall psychopathology with a trend to improve positive symptoms in patients with schizophrenia. Because the number of studies was small, additional controlled clinical trials with larger numbers of patients are indicated.

Background: Generalized anxiety disorder (GAD) is a common and serious disease with a lifetime prevalence of 4.3% to 5.9%. It is underdiagnosed in primary care., Methods: Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent randomized trials, retrieved by a selective search of the literature., Results: Among psychotherapeutic techniques, various kinds of cognitive behavioral therapy (CBT) have been found useful in controlled trials. The drugs of first choice include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephine reuptake inhibitors (SNRIs), and the calcium-channel modulator pregabalin. Tricyclic antidepressants are also effective but have more adverse effects than SSRIs. Although benzodiazepines are effective anxiolytic agents for short-term use, they should not be given over the long term because of the danger of addiction. Buspirone, an azapirone, was found to be effective in a small number of trials, but the findings across trials are inconsistent. The response rate of GAD to CBT in published studies lies between 47% and 75%, while its response rate to drug treatment lies between 44% and 81%., Conclusion: The treatment of GAD with CBT and drugs is evidence-based and has a good chance of improving the manifestations of the disorder.

Our researches have shown that gestational stress causes exacerbation of inflammatory pain in the offspring; the maternal 5-HT1A agonist buspirone before the stress prevents the adverse effect. The serotonergic system and hypothalamo-pituitary-adrenal (HPA) axis are closely interrelated. However, interrelations between inflammatory pain and the HPA axis during the hyporeactive period of the latter have not been studied. The present research demonstrates that formalin-induced pain causes a gradual and prolonged increase in plasma corticosterone level in 7-day-old male rats; twenty-four hours after injection of formalin, the basal corticosterone level still exceeds the initial basal corticosterone value. Chronic treatments of rat dams with buspirone before restraint stress during gestation normalize in the offspring pain-like behavior and induce during the acute phase in the formalin test the stronger corticosterone increase as compared to the stress hormonal elevation in animals with other prenatal treatments. Negative correlation between plasma corticosterone level and the number of flexes+shakes is revealed in buspirone+stress rats. The new data enhance the idea about relativity of the HPA axis hyporeactive period and suggest that maternal buspirone prior to stress during gestation may enhance an adaptive mechanism of the inflammatory nociceptive system in the infant male offspring through activation of the HPA axis peripheral link.

The aim of this study was to evaluate the potential efficacy of the serotonin(1A) (5-HT(1A)) receptor agonist buspirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isoflurane-anesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Morphologically intact CA1/CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses (p<0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI.

Background: Chronic spinal cord injury may be complicated by weight loss, muscle atrophy, and bone loss., Objective: The authors identified a combination pharmacotherapy using buspirone, carbidopa, and L-DOPA (BCD) that elicits bouts of locomotor-like movements in spinal cord-transected (Tx) mice. They then evaluated the effects of 8 weeks of treadmill training in Tx mice that received BCD or BCD + clenbuterol, a monoaminergic agent with anabolic properties, on locomotor function, muscle atrophy, adipose tissue loss, and bone density measures., Methods: Induced locomotor movement, adipose tissue, skeletal muscle, and femoral bone properties were compared in unoperated control mice, operated controls (untreated, untrained Tx mice), and 2 groups of treated, trained Tx mice (Tx + BCD, Tx + BCD + clenbuterol) that also received training., Results: BCD- and BCD + clenbuterol-treated mice showed comparable levels of locomotor movements that significantly improved over time. Soleus muscle mass and soleus and extensor digitorum longus cross-sectional area significantly increased in both groups of BCD-treated mice, with greater effects in BCD + clenbuterol-treated animals. Fiber type conversion, adipose tissues, bone mineral density, and content were reduced in all Tx groups compared with unoperated control mice., Conclusion: These findings suggest that locomotor movement and muscle properties can be restored to near-normal levels after several weeks of BCD treatment, regular training, and clenbuterol in completely paraplegic animals.

A recent randomized clinical trial showed buspirone efficacy in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children. However, results from a recent multi-site controlled clinical trial of transdermal buspirone failed to separate it from placebo in a large sample of children with ADHD. Therefore, due to these inconsistent findings, this study was designed to assess the efficacy of buspirone in the treatment of children with ADHD compared to methylphenidate in a double blind randomized clinical trial. Forty outpatients with a DSM-IV-TR diagnosis of ADHD were study population of this trial. Subjects were recruited from an outpatient child and adolescent clinic for a 6 week double blind, randomized clinical trial. All study subjects were randomly assigned to receive treatment using tablet of buspirone at a dose of 20-30 mg/day depending on weight (20 mg/day for < 30kg and 30 mg/day for > 30kg) (group 1) or methylphenidate at a dose of 20-30 mg/day depending on weight (20 mg/day for < 30kg and 30 mg/day for > 30kg (group 2) for a 6 week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent ADHD Rating Scale IV. Patients were assessed at baseline and at 21 and 42 days after the medication started. Significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores. The changes at the endpoint compared to baseline were: -8.95±8.73 (mean±SD) and -15.60±7.81 (mean±SD) for buspirone and methyphenidate, for Parent ADHD Rating Scale. The changes at the endpoint compared to baseline were: -9.80 ±7.06 (mean±SD) and -22.40±9.90 (mean±SD) for buspirone and methyphenidate, respectively for Teacher ADHD Rating Scale. The difference between the buspirone and methylphenidate groups in the frequency of side effects was not significant except for decreased appetite, headache and insomnia that were observed more frequently in the methylphenidate group. The results of this study suggest that administration of buspirone was less effective than methylphenidate in the treatment of ADHD.

Background: Approximately 20% of stroke patients experience anxiety at some point after stroke., Objectives: To determine if any treatment for anxiety after stroke decreases the proportion of patients with anxiety disorders or symptoms, and to determine the effect of treatment on quality of life, disability, depression, social participation, risk of death or caregiver burden., Search Methods: We searched the trials register of the Cochrane Stroke Group (October 2010), CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (1950 to October 2010), EMBASE (1947 to October 2010), PsycINFO (1806 to October 2010), Allied and Complementary Medicine database (AMED) (1985 to October 2010), Cumulative Index to Nursing and Allied Health (CINAHL) (1982 to October 2010), Proquest Digital Dissertations (1861 to October 2010), and Psychological Database for Brain Impairment Treatment Efficacy (PsycBITE) (2004 to October 2010). In an effort to identify further published, unpublished and ongoing trials, we searched trial registries and major international stroke conference proceedings, scanned reference lists, and contacted select individuals known to the review team who are actively involved in psychological aspects of stroke research, and the Association of the British Pharmaceutical Industry., Selection Criteria: Two review authors independently screened and selected titles and abstracts for inclusion in the review. Randomised trials of any intervention in patients with stroke where the treatment of anxiety was an outcome were eligible., Data Collection and Analysis: Two review authors independently extracted data for analysis. We performed a narrative review. A meta-analysis was planned but not carried out as studies were not of sufficient quality to warrant doing so., Main Results: We included two trials (three interventions) involving 175 participants with co-morbid anxiety and depression in the review. Both trials used the Hamilton Anxiety Scale (HAM-A) to assess anxiety, and neither included a placebo control group. One trial randomised 81 patients to paroxetine, paroxetine plus psychotherapy or standard care. Mean level of anxiety severity scores were 58% and 71% lower in the paroxetine, and paroxetine plus psychotherapy groups respectively compared with those in standard care at follow-up (P < 0.01). The second trial randomised 94 stroke patients, also with co-morbid anxiety and depression, to receive buspirone hydrochloride or standard care. At follow-up, the mean level of anxiety was significantly lower for those receiving buspirone relative to controls (P < 0.01). Half of the participants receiving paroxetine experienced adverse events that included nausea, vomiting or dizziness; however, only 14% of those receiving buspirone experienced nausea or palpitations. No information was provided about the duration of symptoms associated with adverse events., Authors' Conclusions: There is insufficient evidence to guide the treatment of anxiety after stroke. The data available suggest that pharmaceutical therapy (paroxetine and buspirone) may be effective in reducing anxiety symptoms in stroke patients with co-morbid anxiety and depression. No information was available for stroke patients with anxiety only. Randomised placebo controlled trials are needed.

Introduction: Up to one in five people may have generalised anxiety disorder (GAD) at some point, and most have other health problems. Less than half of people have full remission after 5 years. GAD may have a genetic component, and has also been linked to previous psychological or other trauma., Methods and Outcomes: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for GAD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA)., Results: We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions., Conclusions: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: abecarnil, antidepressants (duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, opipramol, paroxetine, sertraline, and venlafaxine), antipsychotic drugs (trifluoperazine), applied relaxation, benzodiazepines, buspirone, cognitive behavioural therapy, hydroxyzine, and pregabalin.

Background: Generalised anxiety disorder (GAD) is a common chronic long-term psychiatric disorder, particularly frequent in primary care. There are several treatment options available, both non-pharmacological (i.e. cognitive behavioral therapy) and pharmacological. Among the pharmacological interventions, antidepressants, buspirone and benzodiazepines (BDZs) have been studied in GAD. Hydroxyzine is an anti-histamine medication which has been used in the treatment of anxiety., Objectives: 1. To determine the efficacy of hydroxyzine in comparison with placebo or any other active agent in alleviating the acute symptoms of GAD. 2. To review acceptability of treatment with hydroxyzine in comparison with placebo or any other active agent. 3. To investigate the adverse effects of hydroxyzine in comparison with other active agents., Search Strategy: The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 1 March 2010. The author team ran complementary searches on MEDLINE, CINAHL and PsycINFO and checked reference lists of included studies, previous systematic reviews and major textbooks of anxiety disorders. Personal communication with pharmaceutical companies and experts in the field was also undertaken., Selection Criteria: Randomised controlled trials allocating patients with GAD to hydroxyzine versus placebo and/or any other anxiolytic agent., Data Collection and Analysis: Two authors independently extracted data. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (such as the number of patients who responded to treatment or remitted), acceptability (the number of patients who failed to complete the study) and tolerability (side effect profile)., Main Results: The search yielded 39 studies. We included five studies in the review with a total of 884 participants. We excluded 31 studies and designated three as awaiting assessment. The data from the included studies provide some evidence that hydroxyzine is more effective than placebo for GAD (odds ratio (OR) 0.30, 95% CI 0.15 to 0.58) and that it is also acceptable/tolerable (OR 1.00, 95% CI 0.63 to 1.58) (OR 1.49, 95% CI 0.92 to 2.40). Compared to other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in terms of efficacy, acceptability and tolerability (hydroxyzine vs chloridiazepoxide: OR 0.75, 95% CI 0.35 to 1.62; hydroxyzine vs buspirone efficacy OR 0.76, 95% CI 0.40 to 1.42). In terms of side effects, hydroxyzine was associated with a higher rate of sleepiness/drowsiness than the active comparators (OR 1.74, 95% CI 0.86 to 3.53). There was, however, a high risk of bias in the included studies., Authors' Conclusions: The included studies did not report on all the outcomes that were pre-specified in the protocol for this review. Even though more effective than placebo, due to the high risk of bias of the included studies, the small number of studies and the overall small sample size, it is not possible to recommend hydroxyzine as a reliable first-line treatment in GAD.